03 第三章 安全无毒化学品的设计.ppt

第1页：第三章 安全化学品的设计

Chapter 3 Designing Safer Chemicals

第2页：第三章 章节导航

General Principles for Designing Safer Chemicals Methods for Designing Safer Chemicals Chapter 3 Designing Safer Chemicals

第3页：3.1 总原则：两条途径

3.1 General Principles for Designing Safer Chemicals

• Two main ways to avoid Hazard and Toxicity
• 1：make it not possible to enter the body,
• 2：make it not possible to affect the bio-chemical and physiological processes(生物化学和生理过程) hazardous ly.
• to human beings, to environment Direct hazard & Indirect hazard

第4页：降低暴露的设计

• They refer to the reduction in exposure by designing chemicals that influence important physical and chemical properties related to environmental distribution and the up-take of the chemical by man and other living organisms. External considerations General Principles for Designing Safer Chemicals

第5页：结构设计的取向

• Structural designs or redesigns:increase degradation rates and those that reduce volatility（挥发性）, persistence in the environment or conversion in the environment to biologically active substances External considerations
• Molecular designs :reduce or impede（妨碍）absorption by man, animals and aquatic life（水生生物）also represent important external considerations.

第6页：外部考量：环境分布

External considerations: Reduction of exposure or accessibility

• A. Properties related to environmental distribution/dispersion
• 1. Volatility/density/melting point
• 2. Water solubility
• 3. Persistence/biodegradation
• a. oxidation, b. hydrolysis,
• c. microbial degradation
• 4. Conversion to biologically active substances
• 5. Conversion to biologically inactive substances

第7页：外部考量：生物摄取

• B. Properties related to uptake by organisms
• 1. Volatility
• 2. Lip oph ili city（亲油性）
• 3. Molecular size
• 4. Degradation
• a. hydrolysis（水解）, b. Effect of p H,
• c. susceptibility to digestive enzymes（消化酶）External considerations: Reduction of exposure or accessibility

第8页：外部考量：吸收途径

• C. Consideration of routes of absorption by man, animals or aquatic life
• 1. Skin/eyes
• 2. Lungs
• 3. Gastrointestinal tract（消化系统）
• 4. Gills(鳃) or other specific routes External considerations: Reduction of exposure or accessibility

第9页：外部考量：减少杂质

• D. Reduction/elimination of impurities
• 1. Generation of impurities of different chemical classes
• 2. Presence of toxic homolog s（同系物）
• 3. Presence of geometric, conformation al or stereoisomer s(几何、构象及光学异构体) External considerations: Reduction of exposure or accessibility

第10页：生物集聚与生物放大

• Bio accumulation（生物集聚）or
• Bio-magnification (生物放大):
• It refers to the increase of tissue concentration of a chemical as it progresses up the food chain. External considerations:

第11页：氯化烃类的组织蓄积

• It is well known that certain chemicals, for example chlorinated pesticides and other chlorinated hydrocarbons, will be stored in the tissues（组织）of a wide range of living organisms and may accumulate to toxic level.
• This phenomenon is exacerbated（恶化）by the fact that the lower forms of life or the organism at lower troph ic（营养的）stages are subsequently consumed as food by fish, mammals and birds.
• These species in turn may be consumed by human. External considerations:

第12页：低等与高等生物的放大

• Hence, the substances of concern may both bio-accumulate in lower life forms and bio magnify or increase their concentration in higher life forms by orders of magnitude as they accumulate and migrate up the food chain. External considerations:

第13页：内部考量：分子操作

• They generally include approaches using molecular manipulations to facilitate:
• Bio de toxic ation
• The avoidance of direct toxicity
• The avoidance of indirect bio-toxicity orbio-activation internal considerations:

第14页：促进解毒与排泄

Internal considerations-Prevention of toxic effects

• A. Facilitation of de toxic ation
• 1. Facilitation of excretion（排泄）
• a.selection of hydrophilic(亲水的)compounds
• b.facilitation of conjugation/acetyl ation
• conjugated with:glucuronic acid(葡萄糖醛酸)
• sulfate(硫酸盐),amino acid
• to accelerate urinary（泌尿器的）orbi liar y(胆汁的)excretion
• c.other considerations

第15页：促进生物降解

• 2. Facilitation of bio degradation
• a.oxidation
• b.reduction
• c.hydrolysis Internal considerations-Prevention of toxic effects

第16页：避免直接毒性

• B. Avoidance of direct toxic ation
• 1. Selection of non-toxicchemicalclassesorparentcompounds
• 2. Selection of non-toxic functional groups
• a.avoidance of toxic groups
• b.plannedbiochemicaleliminationoftoxicstructurethroughthenormalmetabolismoftheorganismorstrategicmolecularrelocationofthetoxicgroup
• c.structuralblockingoftoxicgroups
• d.alternativemolecularsitesfortoxicgroups Internal considerations-Prevention of toxic effects

第17页：间接生物毒性

• Indirect bio toxic ation—bio activation
• It describes the circumstances where a chemical is not toxic in its original structural form but becomes toxic after in vivo transformation to a toxic meta boli te（代谢物）.
• Bio activation represents a characteristic mechanism for the toxicity of many carcinogenic(致癌的), mutagenic（诱变的）, and teratogen ic（畸胎的）chemicals. Internal considerations-Prevention of toxic effects

第18页：避免生物活化

• C. Avoidanceofindirectbiotoxication(bio act i ovation)
• 1. Avoidingchemicalswithknownactivationroutes
• a.highlyelectrophilicornucleophilicgroups
• b.unsaturated bonds
• c.other structural features
• 2. Structuralblockingofbioactivation
• Incorporationofstructuralmodificationsthatpreventbioactivation Internal considerations-Prevention of toxic effects

第19页：合成化学家的机会

Opportunities for the synthetic chemist

• Both the external and internal considerations provide
• a wide range of opportunities and approaches to the synthetic chemist for designing chemical structures that reduce or eliminate the toxicity of industrial and commercial chemicals.
• e.g. both properties that reduce exposure and one or more properties that facilitate excretion or metabolic deactivation.

第20页：安全性与功效的协调

• The effective harmonization（一致）of the safety considerations and of complex living organisms with the efficacy considerations of chemical structures for industrial and commercial purposes is expected to achieve.
• Delicate（精巧的）balance between safety and efficacy
• Data and information on the structure-biological activity relationship of these same chemicals at molecular level Opportunities for the synthetic chemist

第21页：3.1.2 设计基础的建立

3.1.2. Building the foundation for designing safer chemicals

• Academia
• Industry
• To bring about a universal practice of the design of safer chemicals, substantial changes must take place in both academia and industry

第22页：三项基础工作

• Increased awareness of the concept of designing safer chemicals
• Establishing the scientific, technical, and economic credibility of the concept
• Effecting a sharper focus on chemicals of concern
• Greater emphasis on mechanistic and SAR research in toxicity
• Revision in the concepts and practice in chemical education
• Major participation by the chemical industry 3.1.2. Building the foundation for designing safer chemicals

第23页：认知现状

Awareness of the concept

• Strict environmental control：alreadybuttheoriginoftheenvironmentalpollutionhasnotyetbeenunderstood
• Green chemistry：Scientificactivitiesandeducationalactivitieshavebeencarriedout,however,vague(含糊的)or blurred（模糊不清的）understandingorevenmisunderstandingsstillgenerallyexistinbothacademiaandindustryaswellasotherarea
• The media：misleadingreportsstillexistandwhatisreallyneededdoesnotappear
• Industry：Although some ideas are accepted,it is far from practice

第24页：科学与经济可信度

Scientific and economic credibility

• The scientific credibility of the concept with respect to academia and the funding institutions must be established.
• The technical and economic feasibility from the standpoint of industry (even private industry) must be demonstrated by real examples.

第25页：聚焦受关注物质

Focus on chemicals of concern

• There must be a sharper focus on, and the establishment of properties for, those chemicals and chemical classes of great concern to human and environment.
• Both industry and academia should focus their attention on those commercial chemicals and chemical classes that have the greatest potential for adverse effects. This involves not only an assessment of the to xico logical properties per se（本身）, but also the extent of the potential exposure to human and th environment.
• Factors such as production volume, use and physico-chemical properties

第26页：机理毒理学研究

Mechanistic to xico logical research

• Research in toxicology must shift its emphasis to mechanistic research, or basic understanding of how a specific chemical or chemical class exerts its to xico logical effect on living organisms at the molecular level.
• It is only with the accumulation of substantial data and information of this nature that the existing principles and concepts of structure-activity relationship (SAR) can be developed further.

第27页：化学教育的改革

Revision of chemical education

• The revision of the existing concepts and practices of chemical education at both undergraduate and graduate level is needed.
• Separated mode of education traditionally
• Although the function of designing safer chemicals can be accomplished through multi-disciplinary collaboration among chemists, toxicologists, pharmacologists, bio-chemists and others, it is believed that individuals with a combined knowledge of chemical structure, industrial application and biological activity at the molecular level will perform more efficiently and effectively.

第28页：化学品的工业功效

Industrial efficacy of chemicals

第29页：新型化学家

Revision of chemical education

• The new hybrid chemist or the to xico logical chemist or simply green chemist must consider both the function of the chemical in its industrial or commercial application and its to xico logical effects in humans and the environment.

第30页：化工行业的参与

Chemical industry involvements

• Majorsupportandparticipationbythechemicalindustryisessential.
• Industrymusttakestepstoincreasetheawarenessoftheconceptamongitsscientistsandmanagement.
• Industrymustencourageitspeopletoapproachtheconceptwithopenmindsandtocarefullyevaluateitspotentialintermsofeconomicandtechnicalfeasibility.

第31页：3.2 安全化学品设计技术

3.2. Techniques in designing of safer chemicals

第32页：理解基础毒性

Techniques in designing of safer chemicals

• To reduce the toxicity of a chemical substance or to make a safer chemical than a similar chemical substance requires an understanding of the basic toxicity.

第33页：策略性结构修饰

• Once toxicity is understood, strategic structural modifications can be made that directly or indirectly attenuate toxicity but do not reduce the commercial usefulness of the chemical.
• There are several approaches that provide the framework for molecular modification needed for the rational design of safer chemicals. Techniques in designing of safer chemicals

第34页：五类设计方法

• To xico logical mechanism
• structural modifications of the molecule
• Reducing Absorption
• Use of toxic mechanism
• Use of structure-activity(toxicity) relationships
• Use of isosteric replacement（等电排置换）
• Use of retro metabolic (soft chemical) design
• Identification of equally efficacious, less toxic chemical substitutes
• Elimination of the need for associated toxic substances Techniques in designing of safer chemicals

第35页：3.2.1 化学物质的毒性

3.2.1. Toxicity of chemicals

• There three fundamental requirements for chemical toxicity:
• Exposure to the chemical substance
• the contact of the substance with the skin, mouth or nostrils(鼻孔)

第36页：生物可利用性

Aspects of chemical toxicity

• Bio-availability
• the ability of a substance to be absorbed into and distributed within a living organism(e.g., humans, fish) to areas where toxic effects are exerted and is a function of the to xico kinetics of the substance
• To xico kinetics: the interrelationship of absorption, distribution, metabolism and excretion.

第37页：内在毒性

Aspects of chemical toxicity

• Intrinsic toxicity
• the ability of a substance to cause an alteration in normal cellular biochemistry and physiology following absorption

第38页：毒性载体与产毒结构

Aspects of chemical toxicity

• Toxic oph ore(毒性载体): a particular structural portion of the substance to which the toxicity is generally attributed.
• To xico geni c（产毒结构): Some substances contain structural features that are not directly toxic but undergo metabolic conversion (bio activation) to yield a toxic oph ore. These structural features are to xico geni c, in that they yield a toxic oph ore subsequent to metabolism.

第39页：毒性的全过程

Aspects of chemical toxicity Exposure Absorption Distribution Metabolism Excretion Chemical-bio molecular interaction in target tissue Toxic effect

第40页：1：吸收

1：Absorption

• It refers to the entrance of the substance into the bloodstream form the site of exposure.
• For a substance to be absorbed and become bio-available, the molecules of the substance must pass through numerous cellular membranes and enter the bloodstream (which is

第41页：吸收的理化前提

• This means that the substance must have the necessary physicochemical properties that enable the molecules comprising the substance to reach their free molecular form, cross biological membranes and enter the blood.1：Absorption

第42页：细胞膜的结构

• The membranes of essentially all cells of the body,particularly those of the skin, the epithelial(上皮的)lining(衬) of the lung, the gastrointestinal tract,capillaries（毛细血管）, and organs, are composed chiefly of lipids(脂肪).
• Therefore, absorption of a chemical substance into the body and its ability to travel through the

第43页：吸收的解剖与生物因素

Absorption

• Anatomical（解剖的）and biological factors are also important in absorption.
• These include surface area, thickness of the membrane barrier, and blood flow.

第44页：影响膜渗透的因素

Physicochemical and biological factors influencing membrane permeation and absorption Physico chemical factors

• Molecular size,
• molecular weight,
• dissociation constant,
• aqueous solubility,
• lip oph ili city(oct an ol/water partition coefficient,i.e.,log P),
• physical state(solid,liquid,gas),
• particle size

第45页：各途径吸收参数

第46页：消化道吸收

Absorption by Gastrointestinal tract

• The gastrointestinal tract is a major site from which chemical substances are absorbed.
• Many environmental toxic ants enter the food chain and are absorbed together with food from the gastrointestinal tract.

第47页：职业暴露的摄入

• In occupational settings, for example, airborne toxic substances enter the mouth from breathing and, if not inhaled, can be swallowed and absorbed from the gastrointestinal tract. Absorption by Gastrointestinal tract

第48页：消化道吸收的生理因素

• The major physiological factors governing the absorption from gastrointestinal tract are surface area and blood flow.
• The largest absorbing surface area and the second greatest blood flow. Absorption by Gastrointestinal tract

第49页：小肠吸收与pH

• The majority of absorption from the gastrointestinal tract occurs from the small intestines.
• The p H of the gastrointestinal tract ranges from about 1-2 in the small intestines, and gradually increases to about 8 in the large intestines. Absorption by Gastrointestinal tract

第50页：pH 对电离的影响

• This variation in influences the extent to which acidic or basic chemical substances are ionized, which influence the extent of absorption.
• Acidic substances are absorbed more readily from the small intestines （p H=1-2）than the large intestines, because they are less dissociated in the small intestines.
• The opposite is true for basic substances.p H=8, absorbed in large intestines. Absorption by Gastrointestinal tract

第51页：影响消化道吸收的性质

Absorption by Gastrointestinal tract

• The physicochemical properties that most significantly affect the extent to which a substance is ads or bed from the gastrointestinal tract include:
• Physical state
• Particle size(for solid)
• The relative lipid to water partition
• Dissociation constant
• Molecular weight
• Molecular size

第52页：水溶性要求

• Asubstancemustbesufficientlywatersolublesuchthatitcanundergorequisitedissociationtoitsfreemolecularfrom.
• Substancesthatareliquidintheirneatform,orarealreadydissolvedinasolvent,aregenerallyabsorbedmorequicklyfromthegastrointestinaltractthanasubstancethatisasolid.
• Generally,substancesthatareintheformofsalts(e.g.,hydrochloride salts,sodium salts,etc.)undergodissolutionmorequicklythantheirun-ionized(neutral)form,and are absorbed more quickly. Absorption by Gastrointestinal tract

第53页：粒径与溶出速率

Absorption by Gastrointestinal tract

• For solid,particlesizealsoaffectstherateofdissolutionandthus,overall absorption.
• The smaller the particle size,thelargerthesurfaceareaandthefasterthedissolutionandabsorptionofthesubstance.
• Largerparticlesizemeanslesssurfaceareaandthereforeaslowerdissolutioninthegastricfluids,and slower or even less absorption.

第54页：脂溶性的作用

Absorption by Gastrointestinal tract

• Lipidsolubilityismoreimportantthanwatersolubilityinregardtoabsorptionfromgastrointestinaltract.
• Themorelipidsolubleasubstanceis,the e better it is absorbed.
• Highly lip o phil ic substances(log P>5),however,areusuallyverypoorlywatersolubleandgenerallyarenotwellabsorbedbecauseoftheirpoordissolutioninthegastricjuice.
• Ontheotherhandchemicalsubstanceswithextremewatersolubilityandverylowlipidsolubilityarealsonotreadilyabsorbed.

第55页：分子量的影响

Absorption by Gastrointestinal tract

• The higher the molecular weight the less a substance is absorbed from the gastrointestinal tract. Assuming sufficient aqueous and lipid solubility, a general guide is:
• Substances with molecular weights less than 300 Dalton s are typically well absorbed.
• Substances with molecular weights ranging over 300-500 are not readily absorbed.
• Substances with molecular weights in the thousands are sparingly absorbed.

第56页：肺的功能与结构

• The function of the lung:exchange oxygen for carbon dioxide.
• The continuous,repetitivebranchingoftheairwaysfromthetrachea(支气管)to the terminal alveoli(肺气泡)(where gas exchange takes place)create an enormous surface area.
• The lungs also receive 100%of the blood pumped from the heart.
• Thethicknessofthealveolacellularmembrane(the absorption barrier of the lung)is only 0.2~0.4μm. Absorption by Gastrointestinal tract

第57页：肺部吸收

Absorption from the lung

• Theseanatomicalandphysiologicalcharacteristicsofthelungenabletherapidandefficientabsorptionofoxygenandfavortheabsorptionofothersubstancesaswell.
• Becausethecellularmembranesofthealveoli(肺气泡)are very thin(0.2∼0.4µm),sothatthedistanceasubstancehastotraversethealveolarmembraneisveryshort. Chemicalsabsorbedthroughthelungcanenterthefloodwithinseconds. Infact,water solubility,rather than lipid solubility,is the more important factor.

第58页：颗粒物在肺的吸收

Absorption from the lung

• For solid substances,
• Particles of 1μm.andsmallermaybeparticularlywellabsorbedfromthelungbecausetheyhavealargesurfaceareaandcanalsopenetratedeepinthenarrowalveolarsacsofthelung(肺气囊).
• Particles of 2 to 5μmaremainlydepositedintothetracheobronchiolar(支气管)regions of the lung,fromwheretheyarecleanedbyretrograde(倒退的)movement of the mucus(粘液)layer in the ciliated(有纤毛的)portions of the respiratory tract.
• Particles of 5μmorlargerareusuallydepositedinthenasopharyngeal(鼻咽)regionandaretoolargeforabsorptionfromthelung,butalsomaybeswallowedandabsorbedfromthegastrointestinaltract

第59页：皮肤吸收

Skin (Dermal) Absorption

• Unlikethelungandthegastrointestinaltract,theprimarypurposeoftheskinisnotfortheabsorptionofsubstancesessentialtolife,butratherprotectionagainsttheexternalenvironment.
• Comparedtothelungandgastrointestinaltract,theskinhasmuchlesssurfaceareaandbloodflow,aswellasaconsiderablythickerabsorptionbarrier.
• Nonetheless,theskinrepresentsasignificantorganofexposureandabsorption.

第60页：经皮吸收的屏障

• Forchemicalstobeabsorbedfromtheskin,they must pass through the 7 cell layers of the epidermis(表皮)beforeenteringthebloodandlymphcapillaries(毛细血管)in the dermis(皮肤). Thisabsorptionbarrierrangesfrom 100 to 1000μm. Theratedeterminingstepisdiffussionthroughthestratumcorneum(horny layer,角质层),whichistheuppermostlayeroftheepidermis. Passage through the 6 other layer is much more rapid. Skin (Dermal) Absorption

第61页：液态与固态的差异

• Substancesthatareliquidintheirneat(纯的)formtendtobeabsorbedmorereadilythansolid,becauseliquidscovermoredermalsurfaceareaandarenearertotheirfreemolecularstatethanaresolid.
• Solid with higher melting points(>125℃)and substances(particularly solids)thatareionicorhighlypolararegenerallynotwellabsorbedfromtheskin.
• Substanceswithgreaterlipophilicity(油溶性)(higher log P)areabsorbedmorereadilyfromtheskinthanarelesslipophilicsubstances. Skin (Dermal) Absorption

第62页：强亲脂性物质

Skin (Dermal) Absorption

• Highly lip o phil ic substances(log P>5),however,canpassthroughthestratumcorneumbutaregenerallytoowaterinsolubletopassthroughtheremaininglayersandenterthebloodstream. Thesesubstancesarepoorlyabsorbedfromtheskin.

第63页：2：分布

2：Distribution

• Distributionreferstothemovementofachemicalthroughthelivingsystemfromitssitesofentryintothebloodstreamfollowingabsorptionfromtheskin,gastrointestinal tract,or lung. Distributionusuallyoccursrapidly.
• Therateofdistributionoforgansortissuesisprimarilydeterminedbybloodflowandtherateofdiffusionoutofthecapillariesintothecellsofaparticularorgan.
• Following absorption,manysubstancesdistributetotheheart,liver,kidney,brain,and other well-per fused(灌注)organs.

第64页：分布的决定因素

Where a substance is distributed?(1)largely dependent upon its Physico chemical Characteristics. lip o phil ic substances: enter the brain. plasma proteins: accumulations in fatty tissues(2) Target Or

第65页：3：代谢

3：Metabolism

• The body has the ability to distinguish between non-food chemical and nutritional substances.
• nutritional substances → non-nutritional substances
• non-nutritional substances : the body will try to eliminate as quickly as possible. urine(尿) and feces(粪): requires greater water solubility
• The body has enzyme-mediated mechanisms for converting substances into more water soluble substances that are easier to excrete. (metabolism or bio transformation）.

第66页：代谢的解毒目的

• The purpose of metabolism de toxic ation:a defense mechanism to convert potentially toxic chemical substances to other substances (metabolites) that are readily excreted.
• The chemical reactions involve
• phase-Ⅰor phase-Ⅱreactions 3：Metabolism

第67页：第一相反应

3：Metabolism Phase-Ⅰreactions

• Phase-Ⅰreactions convert the chemical substances into a more polar meta boli te by oxidation, reduction, or hydrolysis.
• The enzyme systems responsible for Phase-Ⅰreactions are located predominately in the smooth endoplasmic(肉质网) reticulum(网状组织) of the liver. These enzymes are also present in other organs, including the kidney, lung, and gastrointestinal epithelium(上皮细胞).
• Reaction type of metabolism: oxidation catalyzed by the cytochrome P 450

第68页：第二相反应

Phase-ⅡReactions

• Phase-Ⅱreactions involve coupling (conjugation) of the chemical substance or its polar (Phase-Ⅰ) meta boli te with an endogenous(内生的) substrate such as g luc uro nate(葡萄糖酸), sulfate, acetate, or an amino acid, which further increases water solubility and promote excretion.

第69页：第二相反应酶系

• The enzyme systems responsible for Phase-Ⅱreactions are also located predominately in the smooth endoplasmic reticulum of the liver. These enzymes are also present in other organs, including the kidney, lung, and gastrointestinal epithelium.
• Reaction type of metabolism: oxidation catalyzed by the cytochrome P 450 Phase-ⅡReactions

第70页：代谢并非总是解毒

Metabolism

• Note: Metabolism of certain chemical substances does not result in de toxic ation.
• In fact, it is the metabolites of many toxic chemical substances that, ironically, are responsible for the toxicity.
• What does this is referred to as ???

第71页：4：毒物动力学

4：To xico dynamics(毒物动态学)

• The to xico dynamic phase comprises the processes involved in the molecular interaction between the toxic substance and its bio-molecular sites of action and the resultant sequence of biochemical and bio physical events that finally result in the observed toxic effect.
• Receptors(受体):for reversible-acting agents
• Sites of induction of chemical lesions(诱导化学伤害位): for irreversible-acting agents.

第72页：毒性的分子机制

4：To xico dynamics

• In general, a toxic substance exerts its toxicity by the interaction of a particular portion of the molecule or a meta boli te thereof with a cellular macromolecule (enzymes, nuclei acids, or protein, to name just a few), which disrupts normal biochemical function of the macromolecule and ultimately results in the toxicity. What the particular portion is called as???

第73页：图3-2 毒性全过程

Figure 3-2 Aspect of chemical toxicity Exposure Absorption, Distribution, Metabolism, Excretion Exposure phase To xico kinetic phase

第74页：5：排泄

5: Excretion

• Substances are eliminated from the body urine, feces, or breath, bile(胆汁) duct(排泄管), The kidney and bile duct eliminate polar (more water soluble) substances more efficiently than substances with high lipid solubility.
• The kidney is the most important organ for eliminating substances or their meta b lites from the body.

第75页：粪便与肺的排泄

• Substances excreted in the feces are typically the metabolites of absorbed substances, which enter the gastrointestinal tract through the bile duct.
• Excretion from the lung occurs mainly with volatile substances.5: Excretion

第76页：3.3 降低吸收的分子修饰

3.3 Molecular modification that reduce absorption

第77页：减少消化道吸收

Reducing Absorption From the Gastrointestinal Tract

• If oral exposure is expected to be significant, the chemical should be modified to reduce absorption from the gastrointestinal tract. Modifications such as:
• Increasing particle size or keeping the substance in an un-inoni zed form(i.e., free base, free acid)Log P > 5 (not water soluble) > 500 dalton s molecular weightMelting point > 150℃Being solid rather than liquidIncorporation of several substitutes(e.g., -SO 3-) that remain strongly ionized at a p H of 2 or belowContaining s ulf on at es

第78页：减少肺部吸收

Reducing absorption from the lung

• Less volatile low vapor pressure higher boiling point
• Low water solubility
• High melting point ( > 150℃)
• Particle size: > 5µm

第79页：减少皮肤吸收

Reducing Absorption From the Skin

• To be solid
• To be polar or ionized sodium salt of an acid, hydrochloride salt of an amine
• To be water soluble
• To be of low lip oph ili city
• Increasing particle size
• Increasing molecular eight

第80页：3.4 基于毒性机理的设计

3.4 Designing safer chemicals from an under standing of toxic mechanism

第81页：亲电性物质的毒性

1: Toxic Mechanisms Involving Electro phil es(亲电性物质)

• Chemical substances that are electrophilic or are metabolized to electrophilic species are capable of reacting covalently with nucleophilic substituents of cellular macromolecules such as DNA, RNA, enzymes, proteins, and others.
• Examplesofnucleophilicsubstituents:
• thi ol groups(巯基)of c ystein yl(半酰氨酸)residues in protein
• sulfur atoms of methi on yl(甲硫氨酸)residues in protein
• primary amino groups of

第82页：共价结合的毒性后果

1: Toxic Mechanisms Involving Electro phil es(亲电性物质)

• Theseirreversiblecovalentinteractionscanleadtoavarietyoftoxiceffectsincludingcancer,he pato toxicity(肝中毒),he mato toxicity(血液中毒),ne phr o toxicity(肾中毒),reproductive toxicity,and developmental toxicity.
• Fortunately,the

第83页：亲电性化学品

Electrophilic chemical

第84页：表3-4 亲电性取代基

1: Toxic Mechanisms Involving Electro phil es Examples of electrophilic substituents commonly encountered in commercial substances, the reaction they undergo with biological neu cle ophile s, and the resulting toxicity

• Table 3-4

第85页：亲电取代基与毒性关系

Table 3-4 Examples of electrophilic substituents Commonly encountered in commercial substances, the reaction they undergo with biological neu cle ophile s, and the resulting toxicity Electrophile Char

第86页：亲电性不等于毒性

1. Toxic Mechanisms Involving Electro phil es

• In fact：electrophilic substituent≠toxic.
• Its toxicity depends on factors
• Overall bio availability;
• Metabolism;
• Presence of other substituents that may attenuate the reactivity of the electrophilic substituent.

第87页：设计更安全的亲电物质

2：Designing Safer Electrophilic Substances

• Ideally, electrophilic substituents should never be incorporated into a substance.
• However the electrophilic group is often necessary for the intended commercial use of the substance.
• This poses a dilemma for the chemist who wishes to design an electro phil e to react with a nucleophile necessary for intended commercial use but not with biological nucleophile s in individuals exposed to the substance.
• As impossible as this may seem, there are approaches that chemists can use to design safer, commercially-useful electrophilic substances.

第88页：降低亲电性

2：Designing Safer Electrophilic Substances（1）Decreasing the electrophilic it y ofthe molecules Avoiding the interaction of the molecule with the cellular macromolecule in the tissues, thus reducing th

第89页：甲基引入的案例

Example

• Incorporation of a methyl (-CH 3) group on to the α-carbon (to provide a meth a cry late) decreases the electrophilic it y (i.e., reactivity) of the β-carbon and, hence, meth a cry late s (甲基丙烯酸酯) do not undergo 1,4-Michael addition reactions as readily.
• Meth a cry late s often have commercial efficacy similar to a cry late s in many applications, but are less likely to cause cancer because they are less reactive.
• A cry late s(丙烯酸酯), for example, contain an α,β-unsaturated carbonyl system

第90页：丙烯酸酯与甲基丙烯酸酯

A cry late s(丙烯酸酯) CH 2=CH CO OCH 2 CH 3 Carcinogenic (致癌) Meth a cry late s (甲基丙烯酸酯) CH 2=C（CH 3）－COOCH 3 Non-carcinogenicαβαβ

第91页：两种酯的毒性对比

Example

• This point can be demonstrated by comparing ethyl a cry late, which causes cancer in experimental animals, to methyl meth a cry late, which does not cause cancer in a similar assay.
• It seems logical that placement of a methyl group onto the α-carbon of similar α, β-unsaturated systems may also decrease toxicity without sacrificing commercial utility.

第92页：亲电掩蔽策略

（2）electrophilic-masking approach Reactants for the production of the product Masking agents Removing the masking agent The product is regenerated in situ for usein the production, transportation, and

第93页：生物活化为亲电物

3：Toxic Mechanisms Involving Bio activation to Electro phil es and the design of related molecule.

• The majority of biochemical reactions that lead to formation of electrophilic metabolites involve cytochrome(细胞色素) P 450-catalyzed oxidations .
• In these reactions a particular portion of the molecule is bio activated to become an electro phil e.

第94页：易被活化的物质举例

Examples

• 4-Alkyl-Phenol(4-烷基酚)
• Allyl Alcohols(烯醇)
• Prop a rgl Arch oho ls(炔丙基醇)
• Alken s(烯烃) and Alkynes(炔烃)

第95页：构效关系设计法

3.2 Designing Safer Chemicals Using Structure-Activity (Toxicity) Relationships

第96页：活性结构特征

As discussed earlier, substances that are capable of producing a biological effect (p harm a co logical or to xico logical) contain a structural feature that bestows the intrinsic biological property.

第97页：药效团与毒性团

p harm ac oph ore / toxic oph ore

• In the case of drugs,inwhichthebiologicalresponseisdesired,thisstructuralfeatureisreferredtogeneticallyasthepharmacophore.
• Inthecaseofcommercialchemicalsubstances,inwhichthebiologicaleffectisundesired(toxic),thestructuralfeatureisreferredtogeneticallyasthetoxicophore.
• In either case,the structural feature elicits(引起)itsbiologicaleffectthroughinteractionwithaspecificbiomolecularsiteofactiontocausechangesincellularbiochemistry.

第98页：相同毒性团的性质推断

• Substancesthatcontainthesamepharmacophoreortoxicophorearethereforelikelytoexhibitthesamepharmacologicalortoxicologicalproperties.
• The relative potency(力量)amongstthesubstancesintheirabilitytocausethebiologicaleffectmayvarysubstantially.
• Therelativepotencyisdirectlyrelatedtothespecificorincremental(增量的)structuraldifferencesbetweenthesubstancesandtheinfluencethese

第99页：基本原理的定义

General Principle Definition: Theabilityofsubstancesbelongingtothesamechemicalclasstoacauseaparticularbiologicaleffectandtheinfluencethattheirstructuraldifferenceshaveonpotencyarereferredtoasstructure

第100页：机理已知时的关系

General Principle

• The relationship between structure and activity for a given group of substances becomes much clearer when the mechanism of biological action is known.
• Structure-activity relationships are useful for several reasons.

第101页：构效关系的用途一

General Principle

• First,a series of structurally-similar chemicals with a measured p harm a co logical or to xico logical response may allow oneto infer similar p harm a co logical or toxic effects for an analogous untested substance.

第102页：构效关系的用途二

General Principle

• Second,structure-activityrelationshipscanbeusedtodesignnew,analogoussubstancessuchthatthebiologicalactivityiseithermaximized(in the case of drug substances)or minimized(inthecaseofcommercialchemicalsubstances).

第103页：构效关系的应用史

General Principle

• History:
• Structure-activity relationships have been used for decades
• by medicinal chemists in the design of highly efficacious drug substances,
• by the U. S. Environmental Protection Agency for assessing the toxicity of new, untested commercial chemicals prior to commercialization.

第104页：商品化学品中的应用不足

General Principle

• Despite the structure-activity data available for many classes of commercial chemical substances, however, the use of structure-activity relationships has been given little attention by chemists as a rational approach for designing new, less toxic commercial chemical substances.

第105页：定性构效关系

3.2.1 Qualitative Structure-Activity Relationships

• With qualitative structure-activity relationships, the correlation of toxic effect with structure is made by visual comparison of the structures of the substances in the series and the corresponding effects on the toxicity.
• From qualitative examination of structure-activity data the chemist may be able to seea relationship between structure and toxicity, and identify the least toxic members of the class as possible commercial alternatives to the more toxic members.

第106页：定性关系的设计用途

Qualitative Structure-Activity Relationships

• In addition the chemist may infer from the relationship the structural characteristics that reduce toxic potency, there by providing a rational basis to design new, less toxic analogous substances.

第107页：数据量的影响

Qualitative Structure-Activity Relationships

• The larger the data set the more apparent the relationship between structure and activity becomes, but small data sets can nonetheless be quite useful.
• The application of qualitative structure-activity relationships for the design of safer chemicals is demonstrated below using

第108页：定性构效设计举例

Examples of Designing Safer Chemicals using Qualitative SARS

• Poly eth oxy late d Non yl phenol s(聚乙氧基壬酚)
• Gly c idyl Ether s（缩水甘油醚）
• 1，2，4-T riaz ole-3-thi one（1，2，4-三唑-3-硫酮）
• Carboxylic Acids （羧酸）

第109页：聚乙氧基壬酚

Poly eth oxy late d Non yl phenol s(聚乙氧基壬酚)used as emulsifiers/surfactants, predominately in detergents and inks C 9 H 19—C 6 H 4—O(CH 2 CH 2 O)n CH 2 CH 2 OHn=14~29, intense myocardial (心肌的) necrosis

第110页：壬酚的安全化设计

Poly eth oxy late d Non yl phenol s used as emulsifiers/surfactants, predominately in detergents and inks

• Although the mechanism of myocardial toxicity is unknown, the structure-activity relationship data described above are nonetheless useful in designing safer poly eth oxy late d non yl phenol s.
• Clearly, chemists should intentionally design and use poly eth oxy late d non yl phenol s with fewer than 14 or more than 29 eth oxy subunits.

第111页：缩水甘油醚

Gly c idyl Ether s (缩水甘油醚)having the type of structure below CH 2—CH—（O—CH 2）n CH 3 Oused as synthetic reagents for a variety of purposes

第112页：缩水甘油醚的毒性

Gly c idyl Ether s (缩水甘油醚)

• It has been shown that gly c idyl ether s of the type represented above are mutagenic(诱导有机体突变的) and cause testicular(双丸状的)lesions(损害) in rats and rabbits following oral and inhalation administration when the alkyl substituent is an n-octyl (n =7), n-nonyl (n=8) or n-decyl (n=9) .
• These toxic effects are not observed, however, when the alkyl substituent ranges from do dec yl (n=11) to tetra dec yl (n=13).n=7~9，mutagenic, testicular lesions(引发睾丸损伤) n=11~13,no such toxicity

第113页：环氧基团的毒性归属

Gly c idyl Ether s (缩水甘油醚)

• As in the case of poly eth oxy late d non yl phenol s, the mechanism responsible for the toxicity of these gly c idyl ether s is not known, although the ep oxide moiety is almost certainly the toxic oph ore.
• Nonetheless, these structure-activity relationship data are useful for the design of safer gly c idyl ether s. Chemists should avoid designing and using gly c idyl ether s of the type represented above in which the length of the alkyl moiety ranges from 8 to 10 carbons.
• Whenever possible, chemists should design and use gly c idyl ether s in which the length of the alkyl moiety is at least 12 carbon atoms.

第114页：1,2,4-三唑-3-硫酮

l,2,4-T riaz ole-3-thi ones(1，2，4-三唑-3-硫酮)

• The th io car box amide (-C-N) group is found in a variety of commercial substances.
• However, the th io car box amide group is often toxic oph or ic. Many th io car box amides are toxic to the thyroid gland (甲状腺) (i.e.,thy ro toxic(甲状腺机能亢进的)).

第115页：甲状腺毒性表现

l,2,4-T riaz ole-3-thi ones(1，2，4-三唑-3-硫酮)

• The thy ro toxicity is manifested by an inhibition in the thyroid‘s ability to synthesize thyroid hormone(甲状腺激素), which ultimately leads to hypo thyroid is m(甲状腺机能衰退). Infact, some th io car box amides (乙二酰二胺)(e.g.,prop yl th io uracil(丙基硫尿嘧啶),

第116页：甲状腺毒性的机理推测

l,2,4-T riaz ole-3-thi ones(1，2，4-三唑-3-硫酮)

• The specific mechanism by which the th io car box amide moiety is thy ro toxic is unknown, but is believed to involve inhibition of thyroid per oxidase, the enzyme that catalyzes the incorporation of iodine into tyrosine (酪氨酸) residues during thyroid hormone synthesis.

第117页：取代三唑硫酮的毒性数据

The structure and toxicity of substituted l,2,4-T riaz ole-3-thi ones General R 1 R 2 R 3 Relative Toxicity Structure CH 3 HH 1.0 HCH 3 H 1.2 HHCH 3212.0 CH 3 HCH 37.1 HHC 6 H 5－5.7 CH 3 CH 3 H 4.7 HH

第118页：羧酸的毒性

Carboxylic Acids（C）—C—C—C—CO 2 Hn 4 3 2 The toxicity of carboxylic acids includes he pato to xi cities(肝中毒), Fetus deforming(畸胎作用), etc. It is rather safe when C 2 connects to merely H atoms or merely

第119页：定量构效关系

Quantitative Structure-Activity Relationships (QSARs) It is often possible to quantify structure-activity relationship data by correlating into a regression equation(回归方程式)the biological property with

第120页：定量化的前提

Quantitative Structure-Activity Relationships (QSARs) Quant if i cation of structure-activity relationships for a given series of substances depends, therefore, on the successful identification of one

第121页：QSAR 方程示例

Quantitative Structure-Activity Relationships (QSARs) An example of a general QSAR equation is illustrated by equation:log(1/C)=a(x)2+ b(x)+ c(y)+d nrs 1/C:biological activity:(C is a standard concent

第122页：QSAR 的应用一

Quantitative Structure-Activity Relationships (QSARs)

• The application of QSAR:delineate(描绘) the change in biological potency that is (or would be) accompanied by a given change in structure more precisely.
• For example using a QSAR correlation for acute lethal it y（致命性）, one can predict the median（中值的）lethal dose（致命剂量）(LD 50) of an untested substance directly from a physical property of that substance.

第123页：QSAR 的应用二

Quantitative Structure-Activity Relationships (QSARs)

• The application of QSAR:
• it is not necessary to synthesize a substance in order to measure those physicochemical properties
• (Because there are methods for accurately estimating most physicochemical properties directly from structure)

第124页：QSAR 的应用三

Quantitative Structure-Activity Relationships (QSARs)

• Shortly, one can estimate those properties, incorporate them into the appropriate QSAR regression equation and predict the biological property of the substance even though the substance does not exist!
• Medicinal chemists have, for many years, used QSAR as a tool for drug design.
• The U. S. Environmental Protection Agency(EPA) has used QSAR since 1981 to predict the aquatic toxicity of new, untested commercial chemical substances in the absence of test data.

第125页：电子等排置换设计法

3.2 Designing Safer Chemicals Using Iso steric Replacements

• Substances
• similarmolecularandelectroniccharacteristics
• havesimilarphysicalorotherproperties.
• Lang muir called: Phenomenon:iso ster is m(电子等排同物理性质现象),m Compound:isos tere(电子等排物).
• According to Lang muir‘s definition,isosteresaresubstancesorsubstituentsthathavethesamecharge,causedbythesamenumberandarrangementofelectronsandthesamenumberofatoms.

第126页：等排现象的定义演变

Designing Safer Chemicals Using Iso steric Replacements

• Based on molecular orbital theory, several variations of Lang muir's definition of iso ster is m were expressed by others.
• Burger’s definition:
• iso ster is m also encompasses(包含) chemical substances, atoms or substituents that possess near equal or similar molecular shape and volume, approximately the same distribution of electrons, and which exhibit similar physicochemical properties.

第127页：常见电子等排体

• —Hand—F—OH and NH 2
• —CH 3 and—SHand—Cl
• —CH 2—and—NH—and—O—and—S—and—Si H 2—
• —N=and—CH＝and—S—
• In cyclic structure
• CH=CH—and—S—and—O—and—NH—

第128页：苯与噻吩吡啶的等排

Benzene is isosteric with thi oph ene and pyr i dine because the CH=CH-group is isosteric with -N= and -S-atoms Althoughthesesubstancesarestructurallydifferent,someoftheirchemicalpropertiesarenonethel

第129页：7-甲基苯并蒽的案例

• 7-Methyl-benzo[a]anthracene
• (7-甲基苯并蒽),
• is a known carcinogen.7-methyl-l-flu or ob enzo[a]anthracene (7-甲基-1-氟苯并蒽)is not . It is also possible that biological properties may be bestowed(给予), exacerbated(恶化) or attenuated when isosteric modifications are made.

第130页：氟乙酸与乙酸

Acetic acid, on the other hand, is essentially nontoxic but its flu oro-isos tere, flu oro acetic acid, is highly toxic (human oral LD 50 is estimated to be 2-5 mg/kg CH 3 COOH FCH 2 COOH non toxic oral LD 502-5 mg/kg In the body acetic acid reacts with coenzyme A(辅酶 A)(Co A) to form acetyl-Co A(乙酰辅酶 A), which is an important precursor of the citric acid cycle(柠檬酸循环)(a biochemical cascade essential for energy production).

• Flu oro acetic acid is so steric ally similar to acetic acid that it also reacts with Co A, and forms flu oro acetyl-Co A. Flu oro acetyl-Co A enters the citric acid cycle and forms flu oro citrate, which is a potent inhibitor of a con it as e(鸟头酸酶), a critical enzyme of the citric acid cycle

第131页：氟乙酸结构式

FCH 2 COOH

第132页：例3 抗溃疡药物

Example 3 Its potential as a useful anti-ulcer medication was lessened by the toxic effects caused by the th io urea（硫脲）moiety. During the development of anti-ulcer(抗溃疡) medications, for example, it w

第133页：氰基胍置换硫脲

Isosteric replacement of the th io urea moiety with the cyano quan i dine（氰基胍）moiety gave cimetidine,, a potent H 2-receptor antagonist that lacks the toxicity of met i amide. Cimetidine is one of the

第134页：置换的选择性

It is noteworthy that in this example this isosteric modification selectively reduced toxicity without affecting p harm a co logical activity. This is a main reason why isosteric substitution is a com

第135页：金属偶氮染料

Metal liz ed azo dyes(金属偶氮染料)

• Metal liz ed azo dyes: Historically, chromium was a metal of choice in many metal liz ed azo dyes because it imparts the desired color and fastness.
• Hexavalent chromium (Cr VI) was often used in making such dyes. Hexavalent chromium is a known human carcinogen, however, and its commercial use is strictly regulated and highly discouraged by environmental authorities.

第136页：铁替代铬

Metal liz ed azo dyes(金属偶氮染料)

• An alternative metal to chromium in pre metal liz ed azo dyes would have to have the same color and fastness properties as chromium but without the toxicity.
• It has been found that iron (Fe), which is essentially nontoxic, often imparts the same desirable qualities as chromium when used in azo dyes. This is exemplified in comparing azo dyes. Dyestuff 50 has the same color and fastness as 49, but does not contain chromium. Other examples of dyestuff s that use iron rather than chromium are available

第137页：金属偶氮染料的设计

Designing Metal liz ed azo dyes(金属偶氮染料的设计) MM=Cr, toxic M=Fe, non-toxic

第138页：例4 MTI-800 杀虫剂

Example 4

• MTI-800 is a potent insecticide that is also highly toxic to fish (its LC 50 is 3 mg/liter), which limits its commercial usefulness. MTI 800 Fish LC 50=3 mg/ll

第139页：硅置换季碳

• Isosteric substitution of the quaternary carbon with silicon resulted in a new substance that has moderately less insecticidal potency (0.2-0.6) but is considerably less toxic to fish (no fish mortality occurs at concentrations of 50 mg/liter) No mot an it y to fish at 50 mg/l

第140页：软化学设计

2.5 Designing Safer Chemicals Using Retro metabolic Design (i.e., "Soft"Chemical Design) What is the “soft ”?Soft drugs are defined as biologically active, therapeutically useful drugs deliberately de

第141页：软药物的来源

Designing Safer Chemicals Using Retro metabolic Design (i.e., "Soft"Chemical Design)

• A soft drug is usually an analog of a p harm a co logically active substance whose clinical utility is limited by toxicity or adverse effects.
• The soft drug retains the p harm a co logic property but lacks the toxicity because of its rapid de toxic ation..

第142页：理想软药物

• The ideal soft drug:
• desired p harm a co logic property
• converted into non-toxic readily excreta ble (in a single, non-oxidative, metabolic step)
• Using a p harm a co logically active but toxic drug substance as a guide, the design of a soft drug begins with deducing non-toxic metabolites that can be retro metabolically combined (hence the term "retro metabolic design") to form a single structure: the soft drug.
• This relatively new approach to drug design has led to the development of a number of non-toxic, highly useful drug substances

第143页：盐酸十六烷基吡啶

Ce tyl pyr id in i um chloride 盐酸十六烷基吡啶 An effective antiseptic(防腐剂) but is regarded as being quite acutely toxic to mammals because it has a rat oral median lethal dose (LD 50) of 108 mg/kg Using thi

第144页：新化合物的结构设计

Ce tyl pyr id in i um chloride 盐酸十六烷基吡啶

• the design of the new compound captured the important structural elements that are necessary for antiseptic activity (i.e., the pyr id in i um and C-16 alkyl moieties),
• and structural modifications(the pyr id in i um methyl ester) that enable rapid breakdown of the substance to comparatively less toxic substances in mammals

第145页：代谢物的选择

Ce tyl pyr id in i um chloride 盐酸十六烷基吡啶

• Pyr i dine, formaldehyde and te trade can oic acid were chosen as the "metabolites" because they are relatively non-toxic and can be retro metabolically combined into a single easily-hydro l yz able substance (new) that is a soft analog of the old one.
• The side chains of old one and new one are essentially 16 carbons in length, and these substances share the same physicochemical and antiseptic properties.
• They differ greatly, however, in their mammalian toxicity: of the new one is 40 times less toxic than old one (the rat oral LD 50 of 54 is greater than 4000 mg/kg).
• Substance NEW is less toxic than OLD because the pyr id in i um methyl ester moiety undergoes facile hydro ly tic cleavage in the blood to pyr i dine, formaldehyde, and te trade can oic acid.

第146页：软化合物的安全性

The new soft compound LD 50＞4000 mg/kg Safe！

CH 3（CH 2）12－Kept－CH 2－CH 2－Changed to

第147页：软性商品化学品

"soft" commercial substance

• The concept of soft drug or retro metabolic design can be extended to commercial chemical design.
• A "soft" commercial substance could be defined as a substance deliberately designed such that it contains the structural features necessary to fulfill its commercial purpose but, if absorbed into exposed individuals, it will break down quickly and non-oxidative ly to non-toxic, readily excreta ble substances.

第148页：寻找同效低毒替代品

2.6 Identification of Equally Useful, Less Toxic Chemical Substitutes of Another Class

• Another approach to designing safer chemicals is the identification of an equally useful less toxic substance that belongs to another chemical class.
• the focus of this approach is on commercial use(not on molecular modification), and depends upon the successful identification of a less toxic substance of a different chemical class that can fulfill this use.
• This approach may be particularly attractive in situations in which molecular modification cannot eliminate or reduce the toxicity of a substance without having a negative affect on commercial usefulness.

第149页：例1 乙酰乙酸酯替代异氰酸酯

Example 1：Ace to acetates as Substitutes for Isocyanate s in Sealants and Adhesives(用乙酰乙酸酯代替异氰酸酯用作密封剂和粘结剂) Isocyanatesarewidelyusedinindustrialsealants 密封剂 and adhesives 粘结剂. Intheseapplicationsthesea

第150页：异氰酸酯的毒性

Example 1：Ace to acetates as Substitutes for Isocyanate s in Sealants and Adhesives

• A major disadvantage of isocyanate s, however, is their toxicity. Isocyanate s cause cancer(癌症), mutations(变种), pulmonary sensitization(肺敏感), and asthma(气喘) and, as such, pose serious health risks to manufacturing personnel.
• They also require special handling and storage, and have limited package stability and weather ability.

第151页：Tremco 公司的替代方案

Example 1：Ace to acetates as Substitutes for Isocyanate s in Sealants and Adhesives

• The Tre m co Corporation (Beach wood, Ohio)
• Alternative sealant-adhesive:
• This alternative sealant-adhesive system utilizes ace to acetate as a functional equivalent of isocyanate.

第152页：替代方案小结

Example 1：Ace to acetates as Substitutes for Isocyanate s in Sealants and Adhesives

第153页：例2 有机锡防污剂

Example 2: Iso thi az ol ones as Substitutes for Organotin Anti foul ants(用异噻唑酮代替有机锡防污剂)

• The growth of marine organisms on submerged structures such as the hulls(船外壳) of ships can cause increased hydro dynamic drag, which is commonly referred to as fouling(污垢).
• Although seemingly harmless, fouling leads to increased fuel consumption, decreased ship speed, increased vessel servicing and cleaning costs, and increased dry dock time. It is estimated that the U. S. government spends over a billion dollars each year as a result of fouling of its military vessels

第154页：有机锡的毒性

• Anti fouling agents are often applied to hulls of ships to prevent fouling.
• Organotin(有机锡) substances are effective anti fouling agents, but they are highly toxic to mussels, clams, and other non-fouling aquatic species.
• In addition, because many organotin substances are regarded as hazardous wastes, their removal from ships during cleaning operations must be performed carefully and is costly.
• Because of their eco toxicity, the use of organotin anti foul ants has been banned throughout the world.

第155页：异噻唑酮替代

Example 2: Iso thi az ol ones as Substitutes for Organotin Anti foul ants

• The Roh m and Haas Company(Spring House, PA)hasdevotedmuchefforttofindingantifoulingagentsthatarenottoxictonon-fouling aquatic species. Theyhavefoundthatisothiazolones(异噻唑龙)are effective marine anti foul ants.4,5-Dich l oro-2-/i-octyl-4-iso thi az olin-3-one(4,5-二氯-2-正辛基-4-异噻唑-3-酮)isaparticularlyusefulantifoulant.

第156页：异噻唑酮的优点

Example 2: Iso thi az ol ones as Substitutes for Organotin Anti foul ants In addition to being an excellent biocide, it presents little risk to non-fouling aquatic organisms: it decomposes quickly in

第157页：例3 联苯胺染料

Example 3: S ulf on a ted Di amino benz a nili des as Substitutes for Benz i dines in Dyes 用磺化二氨基 N 苯甲酰苯胺代替染料中的联苯胺

• Benz i dine(联苯胺)and many of its con gene rs were at one time widely used in the synthesis of dyestuff s. Their unique color and fastness properties made them particularly useful for this purpose. When it became apparent that benz i dine and a number of its con gene rs(同类物质) are highly carcinogenic their use as synthetic intermediates in dyestuff s dropped drastically

第158页：磺化二氨基苯甲酰替苯胺

S ulf on a ted Di amino benz a nili des as Substitutes for Benz i dines in Dyes

• Many researchers have attempted to find non-carcinogenic alternatives to benz i dines that have the same desired properties as benz i dines.
• S ulf on a ted di amino benz a nili des (磺化二氨基 N 苯甲酰苯胺代替联苯) where recently reported to be useful substitutes for benz i dine in the synthesis of direct dyes.

第159页：磺酸基的降毒推测

S ulf on a ted Di amino benz a nili des as Substitutes for Benz i dines in Dyes

• Although it is not yet known whether these substances are carcinogenic, the s ulf onic acid moiety may make them non-carcinogenic because the carcinogen i city of other aromatic amines is often eliminated by the inclusion of this moiety.

第160页：3.7 消除伴生有毒物质

3.7: Elimination of the Need for Associated Toxic Substances

• Although a chemical substance may not be toxic, its storage, transportation or use may require an associated substance that is toxic (e.g., a solvent such as carbon tetrachloride).
• In such instances it is the associated substance that represents the toxic component. In this approach one needs to somehow eliminate the need for the associated toxic substance.

第161页：替代伴生物

Elimination of the Need for Associated Toxic Substances

• In some cases this could be accomplished by simply identifying an alternative, less toxic associated substance that will serve the same purpose as the toxic substance (e.g., switching from a toxic solvent to a less toxic, equally useful solvent).
• In other cases, more elaborate formulation changes may be necessary.
• In cases where switching to a less toxic associated substance or reformulation is not possible, the original substance may have to be structurally modified to a new substance for which a less toxic associated substance can be used or reformulation is possible.
• These structural modifications should not, of course, impart toxicity.

第162页：课后练习（一）

Exercises

• 1、简答
• 人类避免有害化学品毒性的途径
• 生物放大（聚集）
• 化学品产生毒性的三要素
• 毒性载体（Toxic oph ore）
• 和产毒结构（To xico geni c）
• 构效关系，化学性质描述符
• Lang muir 电子等排同性质原理
• 软化学设计

第163页：课后练习（二）

Exercises

• 2、设计安全有效化学品的外部效应原则的主要内容有那些?
• 3、设计安全有效化学品的内部效应原则的主要内容有那些?
• 4、肠胃、肺和皮肤吸收的特点有哪些？如何通过改变分子性质避免其被吸收？
• 5、消除化学品毒性的 Phase-I 反应和 Phase-II 反应的化学本质是什么？

第164页：课后练习（三）

Exercises

• 6、典型亲电性物质的结构特征有哪些？其引发的中毒化学反应主要有哪些？人体内细胞的哪些结构容易与亲电性物质发生中毒化学反应？
• 7、常见电子等排物有哪些？
• 8、举例说明用无毒无害的物质取代有毒有害物质的重要性和可能性

第165页：课后练习（四）

Exercises 9、某化合物的结构如下，指出其可能引发的中毒反应